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Biomedical subjects

A Weizman

Publications and source records attributed to A Weizman.

At least 37 records · Page 2Linked to original sources
PubMed2002

Preferential transmission of interleukin-1 receptor antagonist alleles in attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, where family data support substantial heritability.(1) To date, association studies focussed mainly on genes regulating dopaminergic neurotransmission.(2)Interleukin-1 (IL-1) activity in the brain has been implicated with differentiation of dopaminergic neurons(3,4) and modulation of central monoaminergic reactivity.(5) We investigated the role of interleukin-1 receptor antagonist (IL-1Ra) gene variable number tandem repeat (VNTR) polymorphism,(6) in a sample of 86 children with DSM-IV ADHD and their parents. Transmission disequilibrium analysis showed increased transmission of the IL-1Ra 4-repeat allele (chi(2) = 4.07, P = 0.04) and decreased transmission of the 2-repeat allele (chi(2) = 4.59, P = 0.03) to affected children. The 4-repeat allele was associated with a significantly increased risk for ADHD (chi(2) = 4.46, df 1, P = 0.035, RR = 1.292, 95% CI 1.01-1.66). The IL-1Ra 2-repeat allele was associated with a significantly decreased risk for ADHD (chi(2) = 4.65, df 1, P = 0.03, RR = 0.763, 95% CI 0.59-0.98). If replicated, this finding may point to a role for brain cytokine activity in the etiopathogenesis of ADHD.

Adolescent↗
PubMed2002

Association between anorexia nervosa and the hsKCa3 gene: a family-based and case control study.

Familial and twin studies have suggested that anorexia nervosa (AN) is a multifactorial disorder with a substantial genetic contribution. The hSKCa3 potassium channel gene, which contains polymorphic CAG repeats in the coding region and is involved in the regulation of neuronal activity, may be a candidate gene for AN because alleles with longer repeats have been found to be associated with mental disorders. Forty Israeli AN family trios were genotyped for the hSKCa3 CAG repeat polymorphism using the haplotype relative risk (HRR) method. The distribution of alleles transmitted to the patients was found to be significantly different from that of the non-transmitted parental alleles, with the longer alleles being over-represented in the patients (Wilcoxon rank test, P = 0.008). The transmission disequilibrium test (TDT) revealed that longer (>19) repeat alleles were preferentially transmitted to AN patients (McNemar's chi(2) = 10.31, P = 0.0013). These results were corroborated by comparing the distribution of alleles between patients and healthy controls (Mann-Whitney test, P = 0.005). Our study suggests that the longer repeat alleles of the hSKCa3 gene may contribute to the genetic susceptibility to AN.

Adolescent↗
PubMed2002

PK 11195 attenuates kainic acid-induced seizures and alterations in peripheral-type benzodiazepine receptor (PBR) protein components in the rat brain.

Peripheral-type benzodiazepine receptors (PBR) are located in glial cells in the brain and in peripheral tissues. Mitochondria form the primary location for PBR. Functional PBR appear to require at least three components: an isoquinoline binding protein, a voltage-dependent anion channel, and an adenine nucleotide carrier. In the present study, rats received intraperitoneal kainic acid injections, which are known to cause seizures, neurodegeneration, hyperactivity, gliosis, and a fivefold increase in PBR ligand binding density in the hippocampus. In the forebrain of control rats, hippocampal voltage-dependent anion channel and adenine nucleotide carrier abundance was relatively low, while isoquinoline binding protein abundance did not differ between hippocampus and the rest of the forebrain. One week after kainic acid injection, isoquinoline binding protein abundance was increased more than 20-fold in the hippocampal mitochondrial fraction. No significant changes were detected regarding hippocampal voltage-dependent anion channel and adenine nucleotide carrier abundance. Pre-treatment with the isoquinoline PK11195, a specific PBR ligand, attenuated the occurrence of seizures, hyperactivity, and increases in isoquinoline binding protein levels in the hippocampus, which usually follow kainic acid application. These data suggest that isoquinoline binding protein may be involved in these effects of kainic acid injections.

Animals↗
PubMed2002

Mianserin or placebo as adjuncts to typical antipsychotics in resistant schizophrenia.

The beneficial effect of atypical antipsychotic drugs (APDs) in treatment-resistant schizophrenia patients has been attributed, mostly, to their relatively high serotonergic (5-HT)2 to dopaminergic (D)2 receptor blockade ratio. We hypothesized that a combination of typical APDs (D2 antagonists) and mianserin, a potent 5-HT2 antagonist, might also exert superior efficacy in this population. Eighteen inpatients with treatment-resistant schizophrenia who had an acute psychotic exacerbation of the disorder received, in a double-blind design, 30 mg/day mianserin (n = 9) or placebo (n = 9) in conjunction with typical neuroleptics [haloperidol (n = 9) or perphenazine (n = 9)]. Clinical status was evaluated before, during, and at the end of 6 weeks of combined treatment with the Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Positive Symptoms (SAPS), Scale for the Assessment of Negative Symptoms and Hamilton Rating Scale for Depression. The typical APD/mianserin group exhibited significantly greater improvement in total BPRS scores (17.6% versus 5.5%; P= 0.03) and a trend towards greater improvement in SAPS scores (35.3% versus 13.0%; P = 0.07). Our study indicates that patients with chronic treatment-resistant schizophrenia who have an acute psychotic exacerbation ('acute-on-chronic') may benefit from the addition of a potent 5-HT2 blocker, such as mianserin, to typical antipsychotics. Our findings may further emphasize the contribution of enhanced 5-HT2 blockade to the 'atypicality' of the atypical APDs and to their greater efficacy in alleviating symptoms of chronic treatment-resistant schizophrenia.

Adult↗
PubMed2001

Protective effect of insulin-like-growth-factor-1 against dopamine-induced neurotoxicity in human and rodent neuronal cultures: possible implications for Parkinson's disease.

Parkinson's disease (PD) is characterized by a progressive loss of 70-80% of dopaminergic (DA) neurons in the substantia nigra. High concentrations of DA were suggested to induce oxidative stress and selective neurodegeneration. We evaluated the effect of insulin-like-growth-factor-1 (IGF-1) on DA toxicity in neuronal cultures. IGF-1 (0.5 microg/ml) suppressed cell death induced by exposure to DA (0.3 mM) after 2 and 4 days, in a rat cerebellar culture. Similarly, IGF-1 (0.5 and 1.0 microg/ml) antagonized DA (0.125 and 0.250 mM) neurotoxicity in a human neuroblastoma cell line (SK-N-SH). Flowcytometric analysis of neuroblastoma cells treated with DA (0.5 mM) showed increased apoptosis, which was significantly reduced by IGF-1. The effect of IGF-1 was associated with increased Bcl-2 expression as indicated by flowcytometry and Western blot analysis. We suggest that IGF-1 possesses a neuroprotective effect against DA-induced toxicity, and may have a potential role in the treatment of PD.

Animals↗
PubMed2001

Specific ligands of the peripheral benzodiazepine receptor induce apoptosis and cell cycle arrest in human colorectal cancer cells.

The peripheral benzodiazepine receptor (PBR) has been implicated in growth control of various tumour models. Although colorectal cancers were found to overexpress PBR, the functional role of PBR in colorectal cancer growth has not been addressed to date. Using primary cell cultures of human colorectal cancers and the human colorectal carcinoma cell lines HT29, LS174T, and Colo320 DM we studied the involvement of PBR in the growth control and apoptosis of colorectal cancers. Both mRNA and protein expression of PBR were detected by RT-PCR and flow cytometry. Using confocal laser scanning microscopy and immunohistochemistry the PBR was localized in the mitochondria. The specific PBR ligands FGIN-1-27, PK 11195, or Ro5-4864 inhibited cell proliferation dose-dependently. FGIN-1-27 decreased the mitochondrial membrane potential, which indicates an early event in apoptosis. Furthermore, FGIN-1-27, PK 11195 or Ro5-4864 increased caspase-3 activity. In addition to their apoptosis-inducing effects, PBR ligands induced cell cycle arrest in the G(1)/G(0)-phase. Thus, our data demonstrate a functional involvement of PBR in colorectal cancer growth and qualify the PBR as a possible target for innovative therapeutic approaches in colorectal cancer.

Adult↗
PubMed2001

Characterization of high-affinity [3H]TBZOH binding to the human platelet vesicular monoamine transporter.

The present study indicates that human platelets can be used as an accessible peripheral model not only for the plasma membrane serotonin transporter, but also for the vesicular monoamine transporter. The vesicular monoamine transporter (VMAT2) is responsible for the accumulation of monoamines in the synaptic vesicles. VMAT2 differs from the plasma membrane transporters in its capability to recognize serotonin, histamine, norepinephrine and dopamine with almost the same affinity. Dihydrotetrabenazine (TBZOH) is a very potent inhibitor of VMAT2 that binds with high affinity to this transporter. [3H]TBZOH has been used as a ligand to label VMAT2 in human, bovine and rodent brain. In this study we characterized the pharmacodynamic and pharmacokinetic parameters of [3H]TBZOH binding in human platelets as compared to rat brain. The density (Bmax) and affinity (Kd) of [3H]TBZOH specific binding was assessed by Scatchard analysis. Association and dissociation rate constants (k(on), K(off)) were assessed by kinetic binding studies. In this study high-affinity and saturable binding sites for [3H]TBZOH were demonstrated in human platelets. Both the affinity of [3H]TBZOH to its binding site in platelets (Kd = 3.2+/-0.5 nM) and the kinetic rate constants (K(on) = 2.8 x 10(7) M(-1) min(-1); K(off) = 0.099 min(-1)) were similar to that in rat brain (Kd(striatum) = 1.5 nM; Kd(cerebral cortex) = 1.35 nM; K(on) = 2 x 10(7) M(-1) min(-1); K(off) = 0.069 min(-1)). Only the VMAT2 blockers tetrabenazine and reserpine inhibited [3H]TBZOH specific binding.

Animals↗
PubMed2001

Hormonal regulation of peripheral benzodiazepine receptor binding properties is mediated by subunit interaction.

The peripheral benzodiazepine receptor (PBR) is composed of three subunits with molecular masses of 18, 30, and 32 kDa. Many physiological functions have been attributed to the PBR, including regulation of steroidogenesis. Furthermore, the PBR itself is under hormonal regulation. In the current study, we investigated the role of female gonadal sex hormones in the regulation of PBR expression in steroidogenic and nonsteroidogenic tissues. To accomplish this, adult female rats were pharmacologically castrated using chronic administration of the gonadotropin-releasing hormone agonist decapeptyl (triptorelin-D-Trp(6)-LHRH). Half of these rats received 17beta-estradiol as hormone replacement, while a control group received daily injections of vehicle only. We found that PBR binding capacity dropped by 40 and 48% in ovaries and adrenals, respectively, following decapeptyl administration, as opposed to no change in the kidney. This down-regulation of PBR densities was prevented by estradiol replacement. We did not find evidence for transcriptional, posttranscriptional, and translational mechanisms in this decapeptyl-induced down-regulation. In contrast, immunoprecipitation of the PBR complex, using antibodies against the 18- and 32-kDa subunits of the complex, demonstrated that there were changes in PBR subunit interactions, consistent with the down-regulation of PBR binding capacity. These findings represent a novel hormone-dependent posttranslational regulatory mechanism.

Adrenal Glands↗
PubMed2001

Case control and family-based studies of tryptophan hydroxylase gene A218C polymorphism and suicidality in adolescents.

The association of suicidality with polymorphism A218C in intron 7 of tryptophan hydroxylase (TPH) gene remains controversial. The aim of this study was to use family-based methods to examine this association in adolescents in order to eliminate the difficulty of sampling a control group from the same ethnic population. Eighty-eight inpatient adolescents who recently attempted suicide were assessed by structured interview for detailed clinical history, diagnoses, suicide intent, suicide risk, impulsivity, aggression, and depression. DNA samples were collected from all subjects, from both biological parents of 40 subjects and from one parent of 9 subjects; TPH allele frequencies were calculated and tested for association to phenotype, stratified by severity, using the haplotype relative risk (HRR) and transmission disequilibrium test (TDT) methods (n = 49). The frequencies were also compared for all the Jewish subjects (n = 84) to the known frequencies of these alleles in healthy Jewish populations. There was no significant allelic association of A218C polymorphism with suicidal behavior or other phenotypic measures according to the HRR method (chi-square = 0.094; P = 0.76), the TDT (chi-square = 0.258; P = 0.61), or association analysis to known population frequencies (chi-square = 1.667, P = 0.19 for Ashkenazi, and chi-square = 0.810, P = 0.37 for non-Ashkenazi). Analysis of variance with the Scheffè test demonstrated a significant difference between CC and AA genotypes in suicide risk and depression among the patients (n = 88). The findings suggest that polymorphism A218C has no major relevance to the pathogenesis of adolescent suicidal behavior, but may have a subtle effect on some related phenotypes.

Adolescent↗
PubMed2001

Obsessive-compulsive disorder in hospitalized patients with chronic schizophrenia.

Obsessive-compulsive (OC) symptoms have been observed in a substantial proportion of schizophrenic patients. In this study, we assessed the rate of occurrence of OC symptoms and the interrelationship between OC and schizophrenic symptoms in 68 hospitalized chronic schizophrenic patients. The patients were interviewed with the Structured Clinical Interview for Axis-I DSM-IV Disorders - Patient Edition (SCID-P) and the appropriate rating scales including the Scale for the Assessment of Positive Symptoms, the Scale for the Assessment of Negative Symptoms, the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Barnes Akathisia Scale, the Abnormal Involuntary Movement Scale, and the Social Behaviour Schedule (SBS). Sixteen patients (23.5%) met the DSM-IV criteria for OCD. A comparison of schizophrenic patients with and without OCD showed that the schizo-obsessive patients were significantly (1.7-fold) more impaired in basic social functioning, as reflected by the SBS score. No significant between-group differences for any of the other clinical variables were found. There was no significant correlation between OC and schizophrenic symptoms within the schizo-obsessive subgroup. The mean Y-BOCS score for the patients with both schizophrenia and OCD was within the typical range (22.8+/-1.7) observed in OCD without psychosis. The findings provide further evidence for the importance of the OC dimension in schizophrenia and may have important implications for the application of effective treatment approaches in this difficult-to-treat subgroup of schizophrenic patients.

Adult↗
PubMed2001

Family-based association study of serotonin transporter promoter in suicidal adolescents: no association with suicidality but possible role in violence traits.

The serotonin transporter-linked promoter region polymorphism (5-HTTLPR) is thought to be associated with some serotonin dysfunction-related psychopathologies such as depression and anxiety disorders. Suicide and suicide-related behaviors such as violence, aggression, and impulsivity have been reproducibly associated with serotonin dysfunction and are partially genetic. This study examined the association of 5-HTTLPR with suicidal behavior and related traits in Israeli suicidal adolescent inpatients using the haplotype relative risk (HRR) method that controls for artifacts caused by population stratification. Forty-eight inpatient adolescents who recently attempted suicide were assessed by structured interviews for detailed clinical history, diagnoses, suicide intent, suicide risk, impulsivity, violence, and depression. Blood samples were collected and DNA extracted from patients and their biological parents. The 5-HTTLPR allele frequencies were tested for association with suicidality by the HRR method. In addition, the relationship between genotypes and phenotypic severity of several clinical parameters was analyzed. No significant allelic association of the 5-HTTLPR polymorphism with suicidal behavior was found (chi square = 0.023; P = 0.88). Analysis of variance of the suicide-related trait measures for the three genotypes demonstrated a significant difference in violence measures between patients carrying the LL and LS genotypes (9.50+/-4.04 vs. 5.36+/-4.03; P = 0.029). This study suggests that the 5-HTTLPR polymorphism is unlikely to have major relevance to the pathogenesis of suicidal behavior in adolescence but may contribute to violent behavior in this population.

Adolescent↗
PubMed2001

Aggravation of food-related behavior in an adolescent with Prader-Willi syndrome treated with fluvoxamine and fluoxetine.

UNLABELLED: Prader-Willi Syndrome is a congenital multisystem disorder, characterized by a typical dysmorphism, mental retardation, hyperphagia due to insatiable appetite, and resultant morbid obesity. Psychiatric symptoms include obsessions and temper tantrums. METHOD: Pharmacotherapy is experimental with a few reports of successful fluoxetine treatment. RESULTS: We report an aggravation in the food-related symptoms and a consequent weight gain in an adolescent with Prader-Willi syndrome, who was treated with fluvoxamine and fluoxetine.

Adolescent↗
PubMed2001

Stability of diagnosis: a 20-year retrospective cohort study of Israeli psychiatric adolescent inpatients.

Outcome according to diagnosis and stability of diagnosis were investigated in a follow-back study of 351 adolescents with various psychiatric disorders hospitalized in a closed psychiatric ward. The duration of follow-back was 15-19 years. All diagnoses were based on the ICD-9. Data were collected from the Health Ministry registry and, in the patients who could be located, by structured telephone interview. Special attention was directed at the diagnosis of transient adolescent psychosis (TAP) vs. schizophrenia and prognostic indicators of suicide. The results showed that the most stable diagnosis was anxiety disorder. The stability of the different diagnoses over time was greater between the second and last admission than between the first and last (for patients with three or more admissions). Number of hospitalizations correlated negatively with prognosis. TAP at second admission was an unstable diagnosis; 66% of these patients had a final diagnosis of schizophrenia. However, patients with a diagnosis of TAP at first admission had a higher predictive index score and a higher outcome score than schizophrenic patients. TAP appeared to be a valid diagnostic entity, distinguishable from schizophrenia in course, frequency of suicidal behaviour and social-occupational outcome. Suicide victims had a higher cumulative length of stay than age- and sex-matched non-suicidal patients. Fifty per cent of the suicide victims had a final diagnosis of schizophrenia, compared to 30 per cent for the whole sample. In conclusion, these findings indicate that TAP is associated with a relatively good prognosis and should probably be differentiated from schizophrenia. Further retrospective and prospective studies of adolescent psychiatric inpatients may help delineate the nature and course of psychosis and other psychopathology in this age group.

Adolescent↗
PubMed2001

Acute and repeated swim stress effects on peripheral benzodiazepine receptors in the rat hippocampus, adrenal, and kidney.

Peripheral benzodiazepine receptor (PBR) density has been found to be sensitive to stress. We set out to compare the influences of acute and repeated swim stress on behavior and PBR density. Following acute and repeated swim stress, rats were tested in an elevated plus-maze and an open-field test for anxiety levels, and tissues were collected from the adrenal gland, kidney, and hippocampus for measurements of PBR density. The acute rather than the repeated stress led to robust alterations in PBR density. The largest reduction in hippocampal and adrenal gland PBR density was found one hour after acute stress. In the hippocampus, acute stress caused a biphasic change in PBR density: a robust reduction in PBR density one hour after the acute stress and a distinct elevation in PBR density at 24 hours, while 72 hours after stress the elevation in PBR density appeared to be reduced.

Adrenal Glands↗
PubMed2001

Subjective effects of MDMA ('Ecstasy') on human sexual function.

Sexual function following 3,4-Methylenedioxymethamphetamine (MDMA, or 'Ecstasy') consumption was subjectively evaluated in 35 healthy recreational users (20 men and 15 women, aged 21-48 years) with regard to four major domains of sexual activity: desire, erection (lubrication in women), orgasm and satisfaction. Desire and satisfaction were moderately to profoundly increased by MDMA in more than 90% of subjects. Orgasm was delayed but perceived as more intense. Erection was impaired in 40% of the men. It seems that MDMA impairs sexual performance, in spite of enhancement of sexual desire and the perception of greater satisfaction.

Adult↗
PubMed2001

Association between severity of schizophrenic symptoms and urinary retention.

A case is presented in which severe urinary retention (UR) occurred during an acute psychotic exacerbation of paranoid schizophrenia. The voiding dysfunction was apparent during continuous treatment with unchanged doses of haloperidol, and it completely resolved with the remission of the psychotic symptoms. A clear temporal correlation was evident between the patient's mental status, the Brief Psychiatric Rating Scale (BPRS) score and the degree of the UR as assessed by quantitatively measuring the total daily post-voiding urine residues. We could not relate the UR to any apparent general medical condition or to the haloperidol treatment. The presented data suggests that UR in schizophrenic patients might be the end-result of various psychosis-related mechanisms.

Acute Disease↗